The epidermal growth factor receptor (EGFR or ErbB1 or HER1) is a transmembrane glycoprotein of 170 kDa that is encoded by the c-erbB1 proto-oncogene located in the 7q22 chromosome. EGFR is a member of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases (RTK) which includes HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). These RTKs share a homologous structure that consists of a ligand-binding extracellular domain (ECD), a single span transmembrane domain and an intracellular domain that contain catalytic-kinase domain and a C-terminal tail. HER kinase signaling pathways are initiated by the binding of extracellular ligand that induces receptor homodimerization or heterodimerization with other HER kinase member and transphosphorylation of the intracellular regions. These events generate the initial signal leading to activation of numerous downstream signaling pathways that are critical for cell proliferation and survival.
EGFR is over-expressed in many malignant tumor types of epithelial cell origin such as head and neck, colorectal, lung, ovarian, renal, pancreatic, skin and other solid tumors. EGFR-mediated signaling pathways play a significant role in the progression of tumor growth and metastases, making EGFR a good target for tumor therapy (Baselga, Oncologist, 7:2-8 (2002), Yarden and Sliwkowski, Nat Rev Mol Cell Biol, 2:127-137 (2001)). At present, four EGFR targeting agents including two small molecules tyrosine kinase inhibitors (TKIs) (erlotinib (Tarceva from Genentech and OSI Pharmaceuticals) and gefitinib (Iressa from AstraZeneca and Teva Pharmaceuticals)) and two naked monoclonal antibodies cetuximab (Erbitux from ImClone and BMS) and panitumumab (Vectibix from Amgen)) have been approved for treatment of colorectal cancer, pancreatic cancer, head and neck cancer, and non-small cell lung cancer (NSCLC). These anti-EGFR agents strongly inhibit EGFR activation and downstream signaling. The TKIs compete with ATP for binding to the EGFR's intracellular kinase domain (Baselga and Arteaga, J Clin Oncol, 23:2445-2459 (20005)), whereas the two monoclonal antibodies compete with the EGFR ligands for binding to the receptor (Gill et al., J Biol Chem, 259:7755-7760 (1984), Goldstein et al., Clin Cancer Res, 1:1311-1318 (1995), Prewett et al., Clin Cancer Res, 4:2957-2966 (1998)).
Anti-EGFR therapies are not perfect. Inhibition of EGFR signaling is only effective in certain tumor type. For example, the efficacy of anti-EGFR antibodies is significantly reduced in colorectal cancer patients with KRAS, BRAF, PIK3CA and PTEN mutations (De Roock et al., Lancet Oncol, 11:753-762 (2010), Bardelli and Sienna, J Clin Oncol, 28: 1254-1261 (2010)). Additionally, the activity of small molecule EGFR inhibitors is limited to NSCLC patients with activating EGFR mutations (Linardou et al., Nat Rev Clin Oncol, 6: 352-366 (2009), Paz-Ares et al., J Cell Mol Med, 14: 51-69 (2009), Mok et al., Discov Med, 8: 227-231 (2009)). EGFR therapies also result in skin toxicity. EGFR expression in normal basal epithelial cells of the skin plays a crucial role in normal development and physiology of epidermis, and inhibition of EGFR signaling causes various skin toxicities including acneiform skin rash, skin dryness, pruritus, paronychia, hair abnormality, mucositis and increased growth of the eyelashes or facial hair (reviewed in Li and Perez-Soler, Targ Oncol 4:107-119 (2009)). Although rarely life-threatening, the skin toxicities cause significant physical and psycho-social discomfort that decrease the patient's life quality. Additionally, in around 10% of patients, the skin toxicity is so severe that it requires treatment interruption or discontinuation that impairs the clinical outcomes of EGFR inhibitors.
Accordingly, the need exists for improved anti-EGFR therapy which is harmless to normal tissues but still very effective in treating EGFR overexpressing malignant tumors, in particular, tumors that are resistant to the current EGFR therapies. To address this particular need, the present invention focuses on a unique novel class of EGFR antibodies that are very potent in killing EGFR expressing tumor cells but have no or little impact on normal epithelial cell growth. Furthermore, while the conjugation of the EGFR antibodies of the invention with cytotoxic agents potentiates the anti-tumor activity of these antibodies, it does not cause additional toxicity to normal epithelial cells.